Meta-analysis of genetic association studies on bipolar disorder

Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, USA.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.42). 07/2012; 159B(5):508-18. DOI: 10.1002/ajmg.b.32057
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Numerous candidate gene association studies of bipolar disorder (BP) have been carried out, but the results have been inconsistent. Individual studies are typically underpowered to detect associations with genes of small effect sizes. We conducted a meta-analysis of published candidate gene studies to evaluate the cumulative evidence. We systematically searched for all published candidate gene association studies of BP. We then carried out a random-effects meta-analysis on all polymorphisms that were reported on by three or more case-control studies. The results from meta-analyses of these genes were compared with the findings from a recent mega-analysis of eleven genome-wide association studies (GWAS) in BP performed by the Psychiatric GWAS Consortium (PGC). A total of 487 articles were included in our review. Among these, 33 polymorphisms in 18 genes were reported on by three or more case-control studies and included in the random-effects meta-analysis. Polymorphisms in BDNF, DRD4, DAOA, and TPH1, were found to be nominally significant with a P-value < 0.05. However, none of the findings were significant after correction for multiple testing. Moreover, none of these polymorphisms were nominally significant in the PGC-BP GWAS. A number of plausible candidate genes have been previously associated with BP. However, the lack of robust findings in our review of these candidate genes highlights the need for more atheoretical approaches to study the genetics of BP afforded by GWAS. The results of this meta-analysis and from other on-going genomic experiments in BP are available online at Metamoodics (

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Available from: James B Potash, Sep 29, 2015
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    • "Heritable influences are well established, with heritability estimates ranging between 80-90% (Shih et al., 2004), and these influences are likely to be polygenic in nature (Gibson, 2010). Further research is inhibited by the difficulty of generating large enough data sets to separate true biological signal from background noise (Seifuddin et al., 2012). "
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    ABSTRACT: Background: There is an emerging interest in the use of cellular models to study psychiatric disorders. We have systematically reviewed the application of cellular models to understand the biological basis of bipolar disorder (BD). Method: Published scientific literature in MEDLINE, PsychINFO and SCOPUS databases were identified with the following search strategy: [(Lymphoblastoid OR Lymphoblast OR Fibroblast OR Pluripotent OR Olfactory epithelium OR Olfactory mucosa) AND (Bipolar disorder OR Lithium OR Valproate OR Mania)]. Studies were included if they had used cell cultures derived from BD patients. Results: There were 65 articles on lymphoblastoid cell lines, 14 articles on fibroblasts, 4 articles on olfactory neuronal epithelium (ONE) and 2 articles on neurons reprogrammed from induced pluripotent stem cell lines (IPSC). Several parameters have been studied, and the most replicated findings are abnormalities in calcium signaling, endoplasmic reticulum (ER) stress response, mitochondrial oxidative pathway, membrane ion channels, circadian system and apoptosis related genes. These, although present in basal state, seem to be accentuated in the presence of cellular stressors (e.g. oxidative stress – rote- none; ER stress – thapsigargin), and are often reversed with in-vitro lithium. Conclusion: Cellular modeling has proven useful in BD, and potential pathways, especially in cellular resilience related mechanisms have been identified. These findings show consistency with other study designs (genome-wide association, brain-imaging, and post-mortem brain expression). ONE cells and IPSC reprogrammed neurons represent the next generation of cell models in BD. Future studies should focus on family-based study designs and combine cell models with deep sequencing and genetic manipulations.
    Journal of Affective Disorders 05/2015; 184:36-50. DOI:10.1016/j.jad.2015.05.037 · 3.38 Impact Factor
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    • "Owing to the significant diversity in etiology and clinical presentation of bipolar disorder, investigators have sought to define more homogenous subgroups with the goal of identifying genetic biomarkers, further understanding the neurobiology, and delineating more specifically tailored, and thus more efficacious, treatment regimens (Teixeira et al. 2013; Seifuddin et al. 2012; Geoffroy et al. 2013). "
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    ABSTRACT: Bipolar disorder presents with diverse clinical manifestations. Numerous investigators have sought to identify variables that may predict a more severe illness course. With the objective of studying the clinical characteristics of bipolar patients between South and North America, a comparison was performed between a sample from Argentina (n = 449) and a sample from the United States (n = 503) with respect to demographics and clinical characteristics, including presence of comorbidities. The Argentinian sample had more unfavorable demographics and higher rates of prior psychiatric hospitalization and prior suicide attempt but a better social outcome. However, the sample from the United States had a higher rate of prior year rapid cycling, as well as younger bipolar disorder onset age (mean ± SD, 17.9 ± 8.4 vs. 27.1 ± 11.4 years) and more severe clinical morbidity, though there was no significant difference in terms of the total duration of the illness. Argentinian compared to American patients were taking more mood stabilizers and benzodiazepines/hypnotics, but fewer antipsychotics and other psychotropic medications, when considering patients in aggregate as well as when stratifying by illness subtype (bipolar I versus bipolar II) and by illness onset age (≤21 vs. >21 years). However, there was no significant difference in rate of antidepressant prescription between the two samples considered in aggregate. Although possessing similar illness durations, these samples presented significant clinical differences and distinctive prescription patterns. Thus, though the Argentinian compared to North American patients had more unfavorable demographics, they presented a better social outcome and, in several substantive ways, more favorable illness characteristics. In both samples, early onset (age ≤ 21 years) was a marker for poor prognosis throughout the illness course, although this phenomenon appeared more robust in North America.
    04/2015; 3(1):3-8. DOI:10.1186/s40345-015-0027-z
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    • "Please cite this article in press as: Gatt JM, et al., Specific and common genes implicated across major mental disorders: A review of metaanalysis studies, Journal of Psychiatric Research (2014), effects were found for BDNF Val66Met (Kanazawa et al., 2007; Seifuddin et al., 2012), but both studies were in smaller cohorts relative to the confirmed study suggesting the null findings may be due to sample characteristics rather than a lack of genetic effects (Supplementary Table 3). Null conflicting effects were also found for DAOA (Seifuddin et al., 2012) and PDLIM5 (Shi et al., 2008c) in mixed ethnic groups, and for SLC6A4 5-HTTLPR in Caucasian samples (Lotrich and Pollock, 2004), each of these in larger cohorts than the original confirmed studies suggesting these confirmed effects may be small and/or due to false positive variability. 3.4. "
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    ABSTRACT: Major efforts have been directed at family-based association and case-control studies to identify the involvement of candidate genes in the major disorders of mental health. What remains unknown is whether candidate genes are associated with multiple disorders via pleiotropic mechanisms, and/or if other genes are specific to susceptibility for individual disorders. Here we undertook a review of genes that have been identified in prior meta-analyses examining specific genes and specific mental disorders that have core disruptions to emotional and cognitive function and contribute most to burden of illness- major depressive disorder (MDD), anxiety disorders (AD, including panic disorder and obsessive compulsive disorder), schizophrenia (SZ) and bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). A literature review was conducted up to end-March 2013 which included a total of 1519 meta-analyses across 157 studies reporting multiple genes implicated in one or more of the five disorders studied. A total of 134 genes (206 variants) were identified as significantly associated risk variants for MDD, AD, ADHD, SZ or BD. Null genetic effects were also reported for 195 genes (426 variants). 13 genetic variants were shared in common between two or more disorders (APOE e4, ACE Ins/Del, BDNF Val66Met, COMT Val158Met, DAOA G72/G30 rs3918342, DAT1 40-bp, DRD4 48-bp, SLC6A4 5-HTTLPR, HTR1A C1019G, MTHR C677T, MTHR A1298C, SLC6A4 VNTR and TPH1 218A/C) demonstrating evidence for pleiotrophy. Another 12 meta-analyses of GWAS studies of the same disorders were identified, with no overlap in genetic variants reported. This review highlights the progress that is being made in identifying shared and unique genetic mechanisms that contribute to the risk of developing several major psychiatric disorders, and identifies further steps for progress.
    Journal of Psychiatric Research 09/2014; 60. DOI:10.1016/j.jpsychires.2014.09.014 · 3.96 Impact Factor
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